We have discovered that substances released from the ventromedial hypothalamus can influence the rate of release of hormones from the endocrine parcreas. The presence of these new peptides in the hypothalamus may indicate a hitherto undescribed pathway for controlling levels of insulin and glucagon in the circulation. Preliminary experiments have uncovered several properties of these activities: (1) The insulin release-inhibiting (IRI) activity and the glucagon releasing (GR) activity can be recovered from hypothalamic tissue incubation media and from homogenized hypothalamic tissue. (2) The IRI activity and the GR activity can be destroyed by treatment with several proteolytic enzymes indicating that these substances are peptidic in nature. (3) Gel filtration of hypothalamic extracts has shown that the IRI and GR activities are separable and are two different substances. This proposal covers the steps necessary to define further the actions and chemical nature of these substances by answering the following questions: (1) Are the activities extracted from hypothalamic tissue effective in an in vivo system. (2) What are the chemical and physical properties of the agents responsible for these two activities in terms of chromatographic electrophoretic mobilities, gel-filtration elution positions and other biochemical manipulations. (3) Are the IRI and GR activities effective in the pathophysiological states occuring in the genetically mutant obese and diabetic mice and are these activities associated with the primary dysfunction in these mutant strains.